Developmental and Reproductive Physiology of Small Mammals at High Altitude: Challenges and Evolutionary Innovations Cayleih E

REVIEW Developmental and reproductive physiology of small mammals at high altitude: challenges and evolutionary innovations Cayleih E. Robertson1,* and Kathryn Wilsterman2

ABSTRACT xanthopygus,Krameretal.,1999;Ochotona curzoniae,Cietal., High-altitude environments, characterized by low oxygen levels and 2009). For example, the animal with the highest known distribution in low ambient temperatures, have been repeatedly colonized by small the world is the yellow-rumped leaf-eared mouse (P. xanthopygus, ∼ altricial mammals. These species inhabit mountainous regions year- adult body mass 55 g), which was recently found to inhabit sites round, enduring chronic cold and hypoxia. The adaptations that allow >6700 m above sea level (Storz et al., 2020). small mammals to thrive at altitude have been well studied in non- Integrative studies of ecology, population genetics and reproducing adults; however, our knowledge of adaptations specific physiology have identified numerous adaptations that allow small to earlier life stages and reproductive females is extremely limited. In endotherms to thrive at HA despite significant and pervasive lowland natives, chronic hypoxia during gestation affects maternal physiological challenges (reviewed in McClelland and Scott, 2019). physiology and placental function, ultimately limiting fetal growth. With very few exceptions, studies on these small HA mammals have During post-natal development, hypoxia and cold further limit growth focused exclusively on the traits of non-reproducing adults (Ivy and both directly by acting on neonatal physiology and indirectly via Scott, 2015). In contrast to many HA-native bird species, small HA impacts on maternal milk production and care. Although lowland mammals inhabit mountainous regions year-round, meaning they natives can survive brief sojourns to even extreme high altitude as undergo their entire reproductive cycle under conditions of chronic adults, reproductive success in these environments is very low, and cold and hypoxia. Despite the fundamental importance of lowland young rarely survive to sexual maturity in chronic cold and reproductive success for fitness, the reproduction, growth and hypoxia. Here, we review the limits to maternal and offspring development of these HA-adapted species has been largely ignored. physiology – both pre-natal and post-natal – that highland-adapted For young mammals, who are small and physiologically immature, species have overcome, with a focus on recent studies on high- the cold and hypoxic HA environment poses unique energetic altitude populations of the North American deer mouse (Peromyscus and physiological challenges (both pre-natally and post-natally) maniculatus). We conclude that a combination of maternal and compared with those experienced by adults. As such, developing developmental adaptations were likely to have been critical steps in mammals may require unique physiological solutions to cope with the evolutionary history of high-altitude native mammals. their environment. In addition, the physiology of developing mammals is inextricably linked to that of their mother, who shapes KEY WORDS: Fetal growth, Gestational adaptations, High altitude, both the pre-natal and post-natal environment of her offspring (Wells, Maternal care, Post-natal development 2019; Wolf and Wade, 2009). The adaptive evolution of reproductive traits at altitude is therefore likely to be a function of both maternal Introduction: adaptation to high-altitude environments and offspring physiology, as well as the complex interactions between ‘One reason to focus on the physiology of juveniles and nestlings is the two (Fig. 1, arrows). In this Review, we discuss the energetic and that for most individuals it is the only physiology ever experienced’ physiological challenges posed by chronic hypoxia and cold to reproduction in small mammals, and we review what we know about Hill (1983). the physiological adaptations during gestation and early life that have The abiotic factors characteristic of high-altitude (HA) environments allowed some species to be highly successful at HA. pose significant energetic challenges to their inhabitants. Animals endemic to alpine regions must cope with chronic cold exposure – as Pre-natal challenges ambient temperature drops on average 2°C with every 300 m gain in We have known for nearly a century that altitude directly challenges elevation – alongside unremitting hypobaric hypoxia, which limits the very first steps in mammalian development. At altitude, fetal aerobic metabolism (Körner, 2007). This combination of stressors growth is reduced as much as 30% in lowland-native mammals, (hypoxia and cold) is particularly challenging for small endotherms including mice, rats, guinea-pigs, humans and sheep (Bailey et al., whose high surface area to volume ratios promote rapid heat loss. The 2019; Gilbert et al., 1979; Matheson et al., 2016; Parraguez metabolic demands of this environment routinely push these small HA et al., 2005, p. 200; Royer et al., 2000; Scheffen et al., 1990; Turan _ endotherms close to their V O2,max (see Glossary; Hayes, 1989). Yet, et al., 2017; Weihe, 1965). In addition, many lowland-native rodents despite these energetic challenges, small rodents and lagomorphs are experience increased rates of fetal death when gestating under the animals with the highest altitudinal distributions across numerous experimental hypobaric hypoxia (Gilbert et al., 1979; Kelley and mountain ranges (e.g. Peromyscus maniculatus, Hock, 1964; Phyllotis Pace, 1968; Matheson et al., 2016). Adaptation to altitude has ameliorated fetal growth restriction in the two mammals that have

1Department of Biology, McMaster University, Hamilton, ON, Canada L8S 4K1. been studied to date: highland-adapted human populations (including 2Division of Biological Sciences, University of Montana, Missoula, MT 59802, USA. native Andeans and Tibetans; Moore, 2017b) and multi-generational highland sheep (Parraguez et al., 2005). Although no one has yet *Author for correspondence ([email protected]) examined the degree to which altitude adaptation may protect fetal

C.E.R., 0000-0002-6769-2852; K.W., 0000-0001-7262-9754 growth in any small mammal, the dramatic effects of altitude on fetal Journal of Experimental Biology

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The physiological traits relevant to fetal growth are both maternal Glossary and fetal. Essentially all major maternal physiological systems are Implantation modified by pregnancy to facilitate the metabolic demands of fetal The process by which the blastocyst attaches to and, in some species, growth (for a detailed review, see Napso et al., 2018). In particular, embeds itself within, the uterine wall. Implantation is the first step in the respiratory, cardiovascular and hematological systems all placentation in which connections between maternal and fetal tissue are increase their capacity or otherwise modify their function in order established. It is essential to the further development of the embryo and successful gestation. to facilitate sufficient gas exchange and nutrient delivery to the feto- Tidal volume placental unit (Napso et al., 2018). Thus, the first major challenge to Volume of air taken into the lungs during a single breath. reproduction at altitude is ensuring that systemic changes to Trophoblast maternal physiology can fulfil delivery demands at altitude, where A class of cells that are derived from the outer layer of the blastocyst. the partial pressure of oxygen is lower than at low altitude. Once Trophoblasts differentiate from a general stem cell type into an array of oxygen (and nutrients) reach the site of implantation (see Glossary), specialized trophoblasts that perform specific functions, including facilitating implantation and building the placenta. their delivery and realized utility to the fetus depend on fetal V_ hematology – which is particularly important for oxygen uptake – O2, max Maximal whole-animal oxygen consumption, indicative of maximum and of course on the structure and function of the placenta, which _ capacity for aerobic metabolism. V O2, max can be elicited by exercise or gates nutrient transfer between mother and fetus. _ cold. The exercise and cold-induced VO , max values for a given individual 2 _ are not always the same. Cold-induced VO , max (thermogenic capacity, _ 2 Maternal physiology V O2, summit) is the product of both shivering and non-shivering thermogenesis. Chronic hypoxia at altitude may constrain fetal growth by inhibiting or altering gestational remodeling of maternal physiology, resulting in insufficient gas exchange and nutrient delivery to the implantation site. In humans, changes to maternal respiratory and death rates and growth in lowland species suggest that fetal growth cardiovascular function that occur in lowlanders at altitude are is a critical challenge that highland-resident small mammals must sufficient to match oxygen content in maternal circulation measured overcome. in highlanders (Moore et al., 2001; Zamudio et al., 2007b), In this part of the Review, we draw on literature exploring the suggesting that oxygen availability in maternal circulation is not the effects of gestational hypoxia on the site of placentation in critical challenge for fetal growth at altitude (Postigo et al., 2009; laboratory strains of lowland rodents, and literature focused on Zamudio et al., 2007b; but see Julian et al., 2009). However, the gestational hypoxia and altitude adaptation in humans and sheep. physiological changes required to maintain blood oxygen content The physiological mechanisms underlying adaptive preservation of may confer costs that directly or indirectly limit fetal growth. For fetal growth at altitude in humans and sheep remain poorly resolved; example, increases in hematocrit and hemoglobin content that occur however, there is substantial evidence from these species that in non-pregnant lowland humans and rodents at altitude persist multiple traits are likely to be important (Moore, 2017a). It should during pregnancy (Gilbert et al., 1979; Julian et al., 2009; Nuzzo be noted that these models have some limitations related to their et al., 2018; Royer et al., 2000; Thompson et al., 2016; Zamudio unique reproductive biology and evolutionary history that may et al., 2007b). Elevated hematocrit contributes to a general increase restrict the extent to which patterns in their physiology are likely to in blood viscosity in pregnant women (Kametas et al., 2004), which be shared with small mammals at altitude (see Box 1 for further may increase flow resistance and thus impede local delivery or discussion). exchange of nutrients and gases at the implantation site and in the

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Fig. 1. The cold and hypoxic conditions of high-altitude environments act directly and indirectly on the physiology of small mammals at various life stages. Black arrows denote direct effects; red arrows denote indirect effects. (1) Maternal physiology during gestation; (2) nutrient transfer to the fetus via the placenta; (3) post-natal growth and development; (4) maternal physiology during lactation; (5) nutrient transfer to pups via nursing; (6) adult physiology. To date, only the direct effects of high-altitude adaptation on non-reproducing adults (6) have been well studied. Graphic designed using BioRender. Journal of Experimental Biology

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and functional remodeling of the uterine artery and associated Box 1. Models for gestational adaptations to altitude vasculature are insufficient, it increases the risk of vascular injury There is a long history of studying effects of hypoxia on fetal growth. within maternal and placental blood vessels (Cartwright et al., 2010; However, the established model systems have limited value for Mateev et al., 2006) and directly affects the delivery of nutrients to identifying physiological mechanisms that preserve fetal growth in high the implantation site by limiting blood flow. altitude (HA)-adapted small mammals. Highland populations of humans High altitude appears to inhibit both structural and functional and sheep have been the primary systems for studying HA adaptation and fetal growth. However, what we know about these systems may not remodeling of the uterine artery and associated vasculature at apply to small mammals. The energetic challenges faced by large HA altitude. Women of lowlander ancestry gestating at altitude have mammals are not equivalent to those of smaller species, whose higher smaller increases in uterine artery diameter across gestation than mass-specific metabolic rates drive increased O2 requirements and rates their sea level counterparts (Aksoy et al., 2015; Chen et al., 2002; of heat loss, necessitating active thermogenesis. Additionally, the long Julian et al., 2008; Zamudio et al., 1995, 2007b, 2010) and, relative generation time of humans and sheep relative to that of small mammals to those gestating at sea level, vascular resistance in the uterine means that there has been less opportunity for evolutionary innovation in these groups (the influence of domestication in sheep notwithstanding). artery of mothers at altitude is elevated in guinea-pigs (Turan et al., Both well-studied populations of HA-native humans (Andean, Tibetan) 2017) and humans (Aksoy et al., 2015; Chen et al., 2002; Julian have resided at altitude for 11,000–25,000 years (Beall, 2007), which et al., 2008; Zamudio et al., 1995, 2007b, 2010). Furthermore, the accounts for between 1000 and 2000 generations, and domestic sheep vasodilatory function of the uterine artery is deficient in lowland have resided at HA for no more than 500 generations (Parraguez et al., humans at altitude (Lorca et al., 2019), and the sensitivity of the 2006). In contrast, HA deer mice native to the Colorado Rocky Mountains smooth muscle cells of the uterine artery to changes in blood have been separated from their Great Plains conspecifics for ∼200,000 generations (Natarajan et al., 2015). There has therefore been much pressure is decreased in guinea-pigs under hypoxia (Mateev et al., more opportunity for selection to act on these smaller species with short 2006). In the case of guinea-pigs, we know that these changes generation times. contribute to increased mechanical strain within the vessel (Mateev Research into hypoxia-dependent fetal growth restriction in small et al., 2006). Failure of the uterine artery to sufficiently remodel to mammals has nearly exclusively utilized laboratory rodent strains, which support blood flow during pregnancy may be related to hypoxia- are generally lowland-derived. These studies can thus only provide dependent inhibition of cell replication: DNA synthesis in the insight into lowlander challenges, not adaptative solutions. In addition, uterine artery of pregnant guinea-pigs is lower under chronic these studies primarily focus on the placenta, ignoring maternal acclimatization to the environmental stressor. This focus on the hypoxia (Rockwell et al., 2000). placenta is problematic because maternal gestational physiology, Highland adaptation appears to have modified the sensitivity of which is altered by altitude, determines the environment of the uterine artery remodeling to chronic hypobaric hypoxia. Highland- placenta and fetus, and thus provides critical context for changes to adapted humans are able to achieve larger uterine artery diameters and placental and fetal physiology. Finally, in the case of both laboratory lower resistance indices at altitude (Charles et al., 2014; Dávila et al., rodents and sheep, many studies tend to use relatively short-term 2010; Julian et al., 2009; Moore et al., 2001; Zamudio et al., 2007b). hypoxia exposure (e.g. only the final third of gestation). Short-term hypoxias, particularly nearer term, are problematic for understanding The relevant mechanism(s) are unknown, but in humans an allele for ecologically relevant responses to chronic hypoxia because they the gene PRKAA1 has been linked to larger gestational uterine artery introduce the environmental stressor after the placenta has already diameter and is under positive selection in Andean women (Bigham completed critical developmental processes. et al., 2014). For small mammals, gestational remodeling of the uterine artery diameter and vasodilatory function (and thus blood flow) in each uterine horn is a function of local (i.e. feto-placental) processes placenta. Indeed, elevated maternal hematocrit and/or hemoglobin (Fuller et al., 2009; Whitney et al., 1993), meaning that litter size and levels have been linked to an increased risk of fetal growth the density of implantation sites along each uterine horn may restriction and other complications in humans at altitude (Gonzales contribute to the degree to which the uterine arteries are able to achieve et al., 2012, 2009; Khalid et al., 2016; Laflamme, 2011; Zamudio sufficient remodeling under chronic hypoxia. et al., 1993). Altitude-adapted deer mice and humans are able to preserve arterial oxygen saturation in circulation at altitude without Fetal physiology similar increases to hematocrit thanks to adaptations spanning Fetal hematology is also altered by gestational hypoxia. For the oxygen-transport cascade (Beall, 2007; Bigham et al., 2013; example, fetal hematocrit and hemoglobin content increase at Chappell and Snyder, 1984; Moore, 2017b; Scott et al., 2018; Storz altitude in both humans and guinea-pigs (Gilbert et al., 1979; et al., 2010; Tate et al., 2020), and thus they would not experience Postigo et al., 2009). However, adaptation to altitude does not blunt negative effects of increased blood viscosity and vascular resistance this effect in human fetuses (Postigo et al., 2009), and there is no on placental function at altitude during pregnancy. evidence for adaptations to fetal hemoglobin structure in HA natives Vascular remodeling to increase the diameter or distensibility of (Storz, 2016). Despite this, in humans, Andean fetuses still display blood vessels near the implantation site could moderate some of an increased hemoglobin–oxygen binding affinity at altitude these changes to maternal hematology by altering local stress and relative to ancestrally lowland fetuses at altitude, suggesting that strain and thus flow resistance. On the maternal side, the uterine there are still some unidentified adaptations in fetal physiology artery is a critical site of vascular remodeling that is also well studied (Postigo et al., 2009). This could be important for the maintenance in the context of altitude adaptation. During healthy pregnancy at of fetal–maternal O2 gradients, as many HA-adapted species have sea level, the uterine artery increases in diameter by more than three evolved higher-affinity adult hemoglobin, which could impede O2 times to facilitate blood flows that will be 50–70 times greater at the unloading at the placenta (Storz, 2016). end of pregnancy relative to the non-pregnant state (Boeldt and Bird, 2017; Mandala and Osol, 2012; Osol and Mandala, 2009). Uterine Placenta structure and function artery distensibility, or the ability for the vessel to expand in The placenta plays an important role in determining the effects of response to elevated intraluminal pressure, is also increased altitude on fetal outcomes, both because it is the major mediator of

(Mandala and Osol, 2012; Mateev et al., 2006). When structural nutrient transport between maternal and fetal circulations and Journal of Experimental Biology

3 REVIEW Journal of Experimental Biology (2020) 223, jeb215350. doi:10.1242/jeb.215350 because its structural and functional development are highly alongside functional changes (such as changes to gene sensitive to hypoxia. The placentas of rodents and lagomorphs expression) that further affect nutrient transport to the fetus. In contain two distinct compartments: a vascular compartment, where particular, glucose utilization by the feto-placental unit appears to nutrient exchange occurs, and an endocrine compartment, which be altered by altitude, such that the placenta relies more heavily plays a critical role in connecting maternal and fetal vasculature and upon glucose and delivers less to the fetus (Royer et al., 2000; in organizing maternal physiology. Both these compartments are Sakuragawa et al., 1988; Tissot van Patot et al., 2010; Vaughan modified by gestational hypoxia, although the impact of these et al., 2019; Zamudio et al., 2010, 2006). In addition to nutrient changes on fetal growth is not as clear. In rats and mice, the transporters, the placenta produces a large number of hormones that implantation site and placenta tend to display increased vascularity remodel maternal physiology across gestation. These hormones are under gestational hypoxia (Soares et al., 2017), facilitating greater primarily synthesized by cells derived from the junctional zone blood flow and nutrient delivery and exchange. However, increased (Soares et al., 2017). Placental prolactins are the major family of blood flow may come at a cost of increased endoplasmic reticulum placental hormones responsible for gestational remodeling of stress within the placenta (Matheson et al., 2016; Yung et al., 2012). maternal physiology (Napso et al., 2018), and they are critical for Increased oxidative damage in the placenta at HA has only been facilitating trophoblast–vascular interactions and remodeling reported in laboured placentas, where the ischemia/hypoxia caused vascular structure in and around the placenta (Soares et al., 2017). by the process of labour may drive differences in these markers Broader changes to the transcriptional landscape of the placenta are (Kurlak et al., 2016; Nuzzo et al., 2018; Parraguez et al., 2011; thought, in part, to reflect shifts in the differentation pathways taken Tissot van Patot et al., 2010; Zhou et al., 2013). Placentas from high- by trophoblasts (i.e. the number or proportion of cells adopting altitude pregnancies at mid-gestation or following cesarean sections specific trophoblast sub-types) (Bu et al., 2016; Soares et al., 2017, at term do not appear to experience increased oxidative damage 2006); thus, additional consideration of the effects of hypoxia on (Matheson et al., 2016; Zamudio et al., 2007a). trophoblast cell behavior and function are warranted. At altitude, the vascular compartment of the placenta is also characterized by a reduction in the diameter of fetal capillaries, Preparing for the post-natal period which may increase the surface area to volume ratio of the surface Maternal physiology during gestation is not simply about across which gas and nutrient exchange occurs (Burton et al., 1996; facilitating fetal growth in utero. Fat accretion, remodeling of Espinoza et al., 2001; Khalid et al., 2016; Parraguez et al., 2010; neural circuitry and maturation of the mammary glands towards the Scheffen et al., 1990; Tissot van Patot et al., 2003, 2004). HA- end of gestation set the stage for successful lactation and parental adapted humans display similar decreases in the diameter of fetal care (Napso et al., 2018). Placenta-derived hormones that influence capillaries at altitude (Jackson et al., 1987a,b), suggesting that the these late-gestation processes may therefore also be important increase in the surface area to volume ratio may indeed be adaptive. components of successful reproduction at altitude, particularly in The endocrine compartment of the placenta, termed the altricial species; however, the effects of altitude on late-gestational junctional zone in rodents, tends to undergo hypertrophy under placenta function as it relates to post-natal maternal success have not gestational hypoxia (Soares et al., 2017). Behavior of the invasive yet been explored in any system to our knowledge. trophoblast (see Glossary), a sub-type of trophoblast arising from the junctional zone that is responsible for invading and remodeling Post-natal challenges maternal vasculature, is also critically affected by gestational Once young HA mammals are born, they must contend with chronic hypoxia in species including rats and guinea-pigs. Hypoxia cold and hypoxia, both of which limit post-natal growth and increases the depth of invasive migration into maternal tissues by survival in low-altitude (LA) natives (e.g. Farahani et al., 2008; Hill, these cells (Soares et al., 2017), potentially allowing for more 1972; Weihe, 1965). extensive vascular remodeling. However, chronic hypoxia also The maturity of HA neonates at birth is likely to be an important appears to inhibit the remodeling behavior of these cells (Soares factor influencing the adaptive evolution of post-natal development. et al., 2017; Zhou et al., 2013). Insufficient remodeling by The mammalian inhabitants of the most extreme altitudes are trophoblasts is likely to be harmful for the fetus because it leads primarily altricial, meaning that they are born relatively immature to insufficient blood flow and/or elevated blood pressure, which can with little to no thermoregulatory capacity (Pembrey, 1895). For all collapse the structures across which nutrient and gas exchange altricial rodents, regardless of altitude, the post-natal period is occur; thus, we might expect to find that highland adaptations to precarious. Mortality rates during the first weeks of post-natal altitude should preserve or even expand invasion and remodeling at development in the wild can range from 49% to 96% (e.g. Bendell, the site of implantation. However, in a mouse knock-out for 1959; Howard, 1949). These high mortality rates coincide with the PRL7B1, a signaling molecule that is critical for trophoblast time when many major physiological systems (e.g. thermoregulation, invasion, the mice that lacked invasive trophoblasts displayed respiratory control) are developing and are sensitive to the improved pregnancy success under hypoxia relative to wild-type environment. As a result, although certain traits that are thought to animals (Bu et al., 2016). A major caveat to these findings is that be important adaptations to HA (e.g. high-affinity hemoglobin; Ivy mice do not have extensive trophoblast invasion under normoxia or et al., 2020) may be present at birth in these altricial species, many of hypoxia, and thus it provides limited insight into the adaptive role of these traits do not develop or become functional until much later in trophoblast invasion for species with more extensive invasion, these species (e.g. Adams et al., 1999; Agbulut et al., 2003; Barnard including humans, rats and guinea-pigs. To date, no data exist on et al., 1970; Chew and Spencer, 1967; Dubowitz, 1963; Dzal et al., HA native mice or other species where trophoblast invasion and 2020; Gokhin et al., 2008; Goldspink and Ward, 1979; Hill, 1976; remodeling are more modest, which could speak to this fundamental Lagerspetz, 1966). Given the low likelihood of survival during the question about the extent to which trophoblast invasion contributes post-natal period, anything that can confer a fitness benefit will to fetal growth outcomes at altitude. probably be under strong selection at HA (Hill, 1983). Altitude-dependent structural changes to the lowlander placenta Below we have outlined developmental adaptations in three and surrounding vasculature described above are occurring physiological systems in the well-studied HA-native populations of Journal of Experimental Biology

4 REVIEW Journal of Experimental Biology (2020) 223, jeb215350. doi:10.1242/jeb.215350 the North American deer mouse. Notably, all these systems are also regulation of the tissue and a coordinated suppression of metabolism under selection in adults of this species, and we describe the adult (Robertson et al., 2019; Velotta et al., 2020). In many species of LA traits for comparison. These adult adaptations are reviewed rodents, post-natal exposure to hypoxia or cold alters the rate of BAT extensively in Storz et al. (2019). The post-natal adaptations were maturation: cold tends to accelerate BAT maturation whereas hypoxia discovered using a common garden experimental design, where wild- suppresses it (Denjean et al., 1999; Morrison et al., 2000; Mortola caught HA and LA mice, native to the same latitude but different and Naso, 1997, 1998; Skála and Hahn, 1974). However, BAT altitudes (300 m versus >4300 m above sea level), were bred in function does not appear to be sensitive to rearing environment in captivity for two generations. Pups were compared with the closely highlanders (Velotta et al., 2016). The developmental delay in BAT related but strictly LA white-footed mouse (P. leucopus). These function is coordinated by a suite of regulatory genes that are experiments allowed us to isolate the effects of the environment and under directional selection at HA (Velotta et al., 2020), suggesting ancestry (genotype) on the ontogeny of a physiological trait that suppressing BAT function during development is a functional (Fig. 2A). It is important to note that these studies focus on a adaptation to the HA environment. This is an example of single subspecies of HA deer mouse native to the Colorado Rocky physiological heterochrony, an evolved change in the Mountains (P. maniculatus nebracensis), where gene flow between developmental timing of a physiological trait (Gould, 1977; Spicer, LA and HA elevations is limited. This population has been separated 2006). We discuss the potential adaptive benefits of such a delay from the conspecific LA controls used in these studies for ∼200,000 below. generations (Natarajan et al., 2015). Mitochondrial gene sequence homologies suggest that various HA subspecies of deer mice, native Skeletal muscle phenotype and function to different mountain ranges, tend to be more closely related to each In endotherms, skeletal muscle performs the dual function of other compared with their geographical closest LA counterparts locomotion and thermogenesis via shivering. Many HA-adapted (Natarajan et al., 2015). However, it is unclear whether the mammals and birds have evolved a more oxidative and/or highly developmental adaptations discussed below are common to other vascularized adult muscle phenotype (Hepple et al., 1998; Kayser HA subspecies, particularly P. maniculatus sonoriensis,nativetothe et al., 1991; León-Velarde et al., 1993; Lui et al., 2015; Mahalingam California White Mountains, where gene flow between elevations is et al., 2017; Mathieu-Costello et al., 1998; Scott et al., 2009; Sheafor, _ much more prevalent (Natarajan et al., 2015; Snyder et al., 1982). 2003). In adults, this probably confers both a higher running V O2,max Geographical variation in HA sites is an important factor to consider and a greater capacity and endurance for shivering. Muscle metabolism in future studies. is also altered in HA species, with HA adults having a greater capacity for both lipid and carbohydrate oxidation (Lau et al., 2017; Lui et al., Brown adipose tissue function 2015; McClelland et al., 2017; Schippers, et al., 2012). Adult HA-adapted mice (P. maniculatus) have a higher In deer mice, whole-animal V_ (running and cold induced) is _ O2,max thermogenic capacity (cold-induced V O2,max) than their LA sensitive to HA rearing environment (Chappell et al., 2007; Russel conspecifics (Cheviron et al., 2012, 2013; Hayes, 1989). This et al., 2008). However, the specialized HA muscle phenotype itself is whole-animal trait, which is a function of both shivering and non- genetically fixed (Nikel et al., 2018; Scott et al., 2015). As stated shivering thermogenesis (NST), is under positive selection at HA above, skeletal muscle is immature at birth in altricial species. For (Hayes and O’Conner, 1999), and it improves survival and increases example, in both newborn LA and HA deer mice, muscle fibers are activity levels in the cold (Sears et al., 2006). In deer mice and other small and poorly vascularized, and muscle metabolic phenotype is small rodents, a major component (>50%) of whole-animal not yet established (Robertson and McClelland, 2019). thermoregulatory capacity is brown adipose tissue (BAT)-based In HA deer mice, the characteristic aerobic muscle phenotype of NST (McClelland et al., 2017; Van Sant and Hammond, 2008). adult mice does not appear until several weeks after birth. Up until this BAT is unique to placental mammals though marsupials may point, the skeletal muscles grow at the same rate as those of LA pups contain BAT-like structures (reviewed in Jastroch et al., 2018). BAT (Robertson and McClelland, 2019). However, prior to the phenotype is characterized by lipid-rich brown adipocyte cells with a high divergence, many genes associated with muscle metabolic processes mitochondrial density. These mitochondria express uncoupling are down-regulated in HA pups (Velotta et al., 2020), and – unlike LA protein-1 (UCP-1), which dissipates the proton gradient established pups – young HA mice are unable to shiver. Overall, despite cold- _ by the electron transport chain across the inner mitochondrial induced V O2,maxbeing elevated in HA adults, neonatal HA pups have membrane. This uncouples the production of ATP from the a much lower thermogenic capacity relative to lowlanders, due to oxidation of fuel, creating a futile cycle that generates heat. UCP- delays in both shivering and non-shivering thermogenesis throughout 1 is activated when BAT is sympathetically recruited in response to post-natal development (Fig. 2B). Suppression of thermogenesis lasts cold (Cannon and Nedergaard, 2004). BAT activity is higher in wild from birth until weaning at 3 weeks of age (Robertson et al., 2019). adult HA deer mice compared with wild-caught LA Peromyscus See below for further discussion. (Velotta et al., 2016). BAT is present, although non-functional, at birth in most altricial species and develops faster than skeletal Breathing pattern and O2 sensing muscle (Barnard et al., 1970). As a result of this rapid maturation, A primary challenge that LA natives encounter when they ascend to early thermogenesis in these animals is driven exclusively by BAT- greater altitude is that of efficiently transporting enough oxygen to based NST, whereas shivering thermogenesis matures later. their mitochondria for oxidative phosphorylation. One way in which Surprisingly, in HA deer mouse pups, BAT does not become HA-adapted mammals and birds have overcome this hurdle is by functional until significantly later in development compared with altering respiratory physiology (reviewed in Ivy and Scott, 2015). lowlanders (Robertson et al., 2019). Unlike lowland Peromyscus, For example, HA deer mice and HA plateau pikas (O. curzoniae) who begin to actively thermoregulate at 8 days old (Hill, 1983; have evolved a deeper tidal volume (see Glossary) compared with Robertson et al., 2019), neonatal HA mice cannot use BAT to their LA counterparts (Ivy and Scott, 2017; Pichon et al., 2009). maintain body temperature during early post-natal development. This This altered breathing pattern allows them to take up oxygen more delay in BAT activation appears to be due to reduced sympathetic efficiently compared with lowlanders. Journal of Experimental Biology

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A Genetic adaptation to HA

Common garden conditions

– Adult – Developmental – Maternal environment environment environment

Deacclimated G1 lab-born G2 lab-born wild-caught adults

B )

1 0.25 – min

1 0.20 – g 2 0.15 (ml O 2

. O V 0.10

0.05

Cold-induced 0 5 10 15 20 25 Age (postnatal day)

Key High altitude G2 Low altitude G2

Fig. 2. Testing for physiological adaptations to high altitude during development. (A) A multi-generation (G), common garden experimental design allows us to isolate the effects of ancestral, developmental and maternal environment on a given physiological trait. In the wild, an individual’s phenotype is driven by a complex interaction between genotype and environment, as well as persistent effects of their rearing environment (pre- and post-natal) and carry-over effects of the environment on their mother. Each generation under common garden conditions removes one of these effects until theoretically only genotypic influences on phenotype remain. (B) Using this design, we see that a slower maturation of thermoregulatory mechanisms has evolved in high altitude _ (HA)-adapted Peromyscus maniculatus. The metabolic responses (cold-induced VO2 ) to acute cold exposure (10 min at 24°C, post-natal days 8 and 10; 10 min at −5°C, post-natal days 14 and 21) are reduced throughout post-natal development until weaning (post-natal day 21) in G2 HA-adapted P. maniculatus (Robertson et al., 2019; Robertson and McClelland, 2019; Velotta et al., 2020). These pups are raised under common conditions, so this response is driven primarily by underlying genetic adaptations (Velotta et al., 2020). We hypothesize that suppressing metabolically costly thermogenesis has evolved at HA, to allow pups to conserve energy for growth. Experimental design figure made in BioRender.

During early post-natal development, the breathing pattern of young an increase in ventilation when oxygen levels drop (hypoxic ventilatory mammals is insensitive to hypoxia. The chemosensory cells of the response), are insensitive to hypoxia at birth in all mammals studied to carotid bodies, which normally sense arterial O2 saturation and trigger date (Carrol and Kim, 2013). In HA deer mice, it takes longer for the Journal of Experimental Biology

6 REVIEW Journal of Experimental Biology (2020) 223, jeb215350. doi:10.1242/jeb.215350 carotid bodies to mature, and the ventilatory sensitivity to hypoxia is et al., 2018; P. maniculatus, Dunmire, 1960; Halfpenny, 1980; delayed relative to that of lowlanders (Ivy et al., 2020). Additionally, Robertson et al., 2019). For those species that do not have large litter the more effective altered breathing pattern that is characteristic of adult sizes – for example, HA North American pikas (Ochotona princips, highlanders is not established until several weeks after birth (Ivy et al., average of one to two pups) – mothers still completely deplete their 2020). Interestingly, the delay in the establishment of a mature fat reserves during lactation, suggesting that they are maximizing breathing pattern and sensitivity to hypoxia matches the developmental their reproductive investment (Miller, 1973). delay in the onset of endothermy in HA deer mice. Hypoxia tends to limit milk production in lowland mammals (e.g. Bruder et al., 2008; Moore and Price, 1948; Walton and Uruski, Why delay developmental function of adaptive phenotypes at HA? 1946; Weihe, 1965). Decreases in milk output under hypoxia can be The studies described above show that, at least in one species, partially alleviated by supplementing nursing mothers with a high delaying the maturation of critical physiological systems during the fat diet, which increases milk fat content (Weihe, 1965). LA-native nursing period is likely to be adaptive in HA environments. These wild house mice (Mus musculus) raised for 10 generations in the findings are counterintuitive, particularly because these delays cold (3°C) produce high fat content milk, which improves offspring occur in the systems directly responsible for responding to low growth and body composition (Barnett and Dickson, 1984). It is oxygen and temperature. What are the possible fitness benefits that possible that small HA mammals also increase the fat content of make these delays adaptive? their milk, although this has not been seen in the few large HA Young altricial neonates are not as sensitive to perturbations in mammals studied to date (humans, yaks and dairy cows: Barsila homeostasis as adults. For example, 4-day-old Peromyscus pups can et al., 2014; Bartl et al., 2009; Qiao et al., 2013; Quinn et al., 2016). survive several hours at a body temperature close to freezing without Therefore, the mechanism by which HA mothers produce enough suffering any adverse consequences (Hill, 2017). If cold neonates milk to provision their offspring is unclear. Regardless, the are passively rewarmed by an external heat source (i.e. their energetic cost of lactation at HA is likely to be quite high. mother), they do not incur the metabolic cost that would normally be One way to support the metabolic costs of lactation at HA is a associated with re-warming (Currie et al., 2015; Geiser et al., 2002). complementary increase in food intake. At LA, mammalian mothers At least one other small, altricial mammalian species, the desert remodel their digestive tracts to increase nutrient absorption during hamster (Phodopus roborovskii) has been shown to use a ‘precocial gestation and lactation. Cold exposure has a similar effect on food torpor’ strategy early in post-natal development to save energy in the intake, increasing nutrient assimilation by increasing the size of cold (Geiser et al., 2019). Additionally, most small mammals tend to digestive organs. The combination of lactation and cold stress act be far less sensitive to low oxygen as neonates than as adults synergistically to further increase food intake in rodent mothers (reviewed in Dzal et al., 2020). It is therefore possible that it is (Hammond et al., 1994; Hammond and Kristan, 2000). In fact, it has adaptive for HA neonates to conserve limited energy for growth been suggested that food intake during lactation is limited by a rather than using energy to mount costly physiological responses to mother’s ability to dissipate metabolically produced heat (the heat low oxygen and ambient temperature. Under cold alone, the benefits dissipation limit hypothesis; for a review, see Speakman and Król, of thermoregulation outweigh the metabolic cost: lowland altricial 2010). Therefore, in cold environments, lactating females consume mammals tend to accelerate the maturation of thermoregulatory more food than would otherwise be possible (Johnson and Speakman, systems when reared in the cold (Barnard et al., 1970; Morrison 2001). However, hypoxia is a known anorexic agent, and it decreases et al., 2000), and some cold-adapted species – for example, the food intake in lactating rats (Bruder et al., 2008). In non-lactating adult Norwegian lemming – have evolved the ability to thermoregulate P. maniculatus the increase in food intake seen in the cold is partially earlier after birth than most other altricial rodents studied (e.g. mice, ablated at 3800 m above sea level (Hammond et al., 2001). Rigorous rats or golden hamsters; Lagerspetz, 1966). However, hypoxia also ecological studies of HA females are required to determine whether affects the timing of the development of both thermoregulation food intake during lactation increases in the wild. (Mortola and Naso, 1997, 1998) and the hypoxic ventilatory HA mothers also invest in their offspring through various forms response (Bavis, 2005). We can therefore only speculate that the of maternal care. Many measures of maternal behavior (e.g. time combination of cold and hypoxia at HA makes the suppression of spent nursing, incubating and grooming pups, nest-building) vary lowlander responses the most cost-effective strategy. considerably amongst individual rodents in the laboratory and in the wild (Champagne et al., 2003). For example, wild mice spend more Maternal care from birth to weaning time nursing when population density is low and thus competition During the early post-natal period, HA mammalian mothers with for food is reduced (Stewart and McAdam, 2014). Importantly, in altricial young must act as both a source of heat and as a source of food lowland altricial species, when mothers spend more time foraging, (Hill, 1972). This creates a significant energetic burden for animals pup growth suffers from the combination of less milk and increased _ that already operate close to their V O2,max (Hayes, 1989). In mice, thermoregulatory costs to the pups (Hill, 1972). Rodents also alter milk output during lactation accounts for ∼50% of the energy derived their nest size or complexity in response to low temperatures, and from food (Johnson et al., 2001). In fact, lactation is widely considered those native to cold climates tend to build larger, more complex to be the most energetically costly life stage for a female mammal nests (King et al., 1964; Phifer-Rixey et al., 2018). Variation in (Speakman and McQueenie, 1996). Successfully provisioning maternal care (e.g. grooming) can have long-lasting epigenetic offspring under extreme conditions was likely to have been one of consequences for offspring phenotype, programming metabolism, the critical evolutionary challenges faced by HA-adapted species. the stress response and their own care behavior (reviewed in Short breeding seasons at HA relative to LA sites of the same Champange, 2008). Although maternal behavior is sensitive to latitude limit the number of litters that a HA female can birth each environmental conditions, there is also a genetic basis to many of year. To compensate, it is likely that HA mothers must invest these traits (Bendesky et al., 2017). As such, altered maternal care heavily in the few litters that they have (McLean et al., 2019; Smith phenotypes can evolve in different environments. To our and McGinnis, 1968). Small HA mammals tend to give birth to knowledge, adaptation of maternal behavior to HA has not been larger litters than their LA conspecifics (e.g. P. xanthopygus, Sassi studied, and this would be an interesting area for future research. Journal of Experimental Biology

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Conclusions Bailey, B. A., Donnelly, M., Bol, K., Moore, L. G. and Julian, C. G. (2019). High The combined cold and hypoxic conditions of HA present significant altitude continues to reduce birth weights in Colorado. Matern. Child Health J. 23, 1573-1580. doi:10.1007/s10995-019-02788-3 metabolic challenges to young mammals that specifically limit Barnard, T., Skála, J. and Lindberg, O. (1970). Changes in interscapular brown growth. Maternal physiology is also directly influenced by cold and adipose tissue of the rat during perinatal and early postnatal development and hypoxia. As a result, in HA environments, resource transfer from after cold acclimation I. Activities of some respiratory enzymes in the tissue. Comp. Biochem. Physiol. 33, 499-508. doi:10.1016/0010-406X(70)90367-1 mother to offspring may be limited during both pregnancy and Barnett, S. A. and Dickson, R. G. (1984). Milk production and consumption and lactation, compounding the direct effects of cold and hypoxia on growth of young wild mice after ten generations in a cold environment. J. Physiol. young mammals. Previous research has shown that these 346, 409-417. doi:10.1113/jphysiol.1984.sp015031 environmental effects make it almost impossible for lowlanders at Barsila, S. R., Kreuzer, M., Devkota, N. R., Ding, L. and Marquardt, S. (2014). Adaptation to Himalayan high altitude pasture sites by yaks and different types of HA to successfully reproduce and grow. We propose that for a species hybrids of yaks with cattle. Livest. Sci. 169, 125-136. doi:10.1016/j.livsci.2014.09. to successfully establish at HA, both maternal and developmental 004 phenotypes must evolve together. The fact that very little is known Bartl, K., Gómez, C. A., Aufdermauer, T., Garcia, M., Kreuzer, M., Hess, H. D. about the adaptive strategies used by these animals means there are and Wettstein, H.-R. (2009). Effect of diet type on performance and metabolic traits of Peruvian local and introduced cow types kept at 200 and 3600 m of many exciting avenues for future study. altitude. Livest. Sci. 122, 30-38. doi:10.1016/j.livsci.2008.07.022 Along with the direct impact of cold and hypoxia on each life stage, Bavis, R. (2005). Developmental plasticity of the hypoxic ventilatory response after which we have outlined above, animals living at HA also deal with perinatal hyperoxia and hypoxia. Respir. Physiol. Neurobiol. 149, 287-299. doi:10. 1016/j.resp.2005.04.003 the cumulative effects of prior exposure to HA conditions that can Beall, C. M. (2007). Two routes to functional adaptation: Tibetan and Andean high- affect fitness throughout their lifetime. For example, a pregnant altitude natives. Proc. Natl. Acad. Sci. USA 104, 8655-8660. doi:10.1073/pnas. female who is unable to properly remodel her mammary glands, 0701985104 neural circuitry and fat accretion during gestation due to hypoxia will Bendell, J. F. (1959). Food as a control of population of white-footed mice, Peromyscus leucopus noveboracensis (Fischer). Can. J. Zool. 37, 173-209. be unprepared to provide sufficient nutrients and care to her pups doi:10.1139/z59-021 during lactation. Insufficient maternal remodeling during pregnancy Bendesky, A., Kwon, Y.-M., Lassance, J.-M., Lewarch, C. L., Yao, S., Peterson, could thus exacerbate the effect of cold and hypoxia on nursing and B. K., He, M. X., Dulac, C. and Hoekstra, H. E. (2017). The genetic basis of other care behaviors, further limiting energy transfer to pups that must parental care evolution in monogamous mice. Nature 544, 434-439. doi:10.1038/ nature22074 grow under cold and hypoxia. Females from such litters who survive Bigham, A. W., Julian, C. G., Wilson, M. J., Vargas, E., Browne, V. A., Shriver, to adulthood will be likely to display long-lasting effects on body M. D., Moore, L. G. (2014). Maternal PRKAA1 and EDNRA genotypes are condition that will limit their own future reproductive success. Thus, associated with birth weight, and PRKAA1 with uterine artery diameter and metabolic homeostasis at high altitude. Physiol. Genomics 46, 687-697. doi:10. what happens during a single reproductive attempt will affect the 1152/physiolgenomics.00063.2014 future chances of success for both mother and offspring. Bigham, A. W., Wilson, M. J., Julian, C. G., Kiyamu, M., Vargas, E., Leon- Finally, moving forward, it is important to remember that young Velarde, F., Rivera-Chira, M., Rodriquez, C., Browne, V. A., Parra, E. et al. altricial mammals are not simply small adults. They do not have the (2013). Andean and Tibetan patterns of adaptation to high altitude. Am. J. Hum. Biol. 25, 190-197. doi:10.1002/ajhb.22358 same physiological tools available to cope with environmental Boeldt, D. S. and Bird, I. M. (2017). Vascular adaptation in pregnancy and stressors. As such, any given physiological system (e.g. endothelial dysfunction in preeclampsia. J. Endocrinol. 232, R27-R44. doi:10. thermoregulation) may need to respond very differently to the 1530/JOE-16-0340 Bruder, E., Hoof, J. V., Young, J. and Raff, H. (2008). Epidermal growth factor and same selective pressure across life stages. By focusing exclusively parathyroid hormone-related peptide mRNA in the mammary gland and their on adult physiology, we may miss many of the physiological concentrations in milk: effects of postpartum hypoxia in lactating rats. Horm. innovations that are critical for adaptation in resident species. Metab. Res. 40, 446-453. doi:10.1055/s-2008-1058101 Studies of HA reproduction and development provide an important Bu, P., Alam, S. M. K., Dhakal, P., Vivian, J. 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